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We present here the K9 lymphoma assay, a novel 31-gene targeted next-generation sequencing panel designed for genomic profiling of canine lymphoid neoplasms. Addressing the growing demand for advanced diagnostics in veterinary oncology, this assay enables sensitive identification of known and actionable mutations specific to canine lymphomas, while evaluating its prognostic potential to facilitate diagnosis and prognosis. Our analysis, spanning several B- and T-cell lymphoma histotypes, unveiled distinct mutational landscapes distinguishing tumors derived from immature versus mature lymphocytes. Clustering analysis revealed a shared genetic origin between diffuse large B-cell lymphoma and marginal zone lymphoma, aligning with findings in human lymphomas, with TRAF3 emerging as the most frequently mutated gene across B-cell lymphoma subtypes. Significantly, TP53 mutations demonstrated universal adverse prognostic implications across B-cell lymphomas. Additionally, SETD2 mutations contributed to shorter time-to-progression, underscoring the role of epigenetic dysregulation in B-cell tumors. In T-cell lymphomas, SATB1 and FBXW7 were frequently mutated, warranting further investigation in larger cohorts. Our findings advocate for tailored therapeutic approaches based on the genetic profile, impacting treatment decisions and outcomes in canine lymphoma management. This study provides pivotal insights bridging veterinary and human oncology, paving the way for comprehensive genomic diagnostics and therapeutic strategies in comparative oncology.

Splenic nodular lesions in dogs can be either benign or malignant. They might be discovered incidentally or, in case of rupture, they may lead to hemoabdomen. Nevertheless, splenectomy followed by histopathology is essential for diagnosis and to prevent rupture. Yet, this invasive procedure might be postponed for dogs with benign splenic nodular lesions. Conversely, owners may opt for euthanasia over surgery for malignancies with poor prognosis like hemangiosarcoma. Thus, anticipating diagnosis with non-invasive biomarkers is crucial for proper patient management. In this prospective study, plasma samples were collected from 66 dogs with histologically confirmed splenic nodular lesions. A canine-specific ELISA kit was applied to assess nucleosome concentration, with histopathology of the spleen serving as the gold standard. Nucleosome concentration was found to be significantly higher in dogs with malignant splenic nodular lesions, particularly in those with hemangiosarcoma and other malignancies. The presence of hemoabdomen, more prevalent in dogs with splenic malignancy, also resulted in increased plasmatic nucleosome concentrations. Plasma nucleosomes could serve as a biomarker for detecting malignant splenic nodular lesions in dogs. More research is needed to understand how nucleosome concentration relate to disease stage and prognosis in dogs with hemangiosarcoma.

Background Risk factors for oral squamous cell carcinoma (OSCC) in cats are derived from a single study dated almost 20 years ago. The relationship between inflammation of oral tissues and OSCC is still unclear. Objectives To investigate previously proposed and novel potential risk factors for OSCC development, including oral inflammatory diseases. Animals Hundred cats with OSCC, 70 cats with chronic gingivostomatitis (CGS), 63 cats with periodontal disease (PD), and 500 controls. Methods Prospective, observational case‐control study. Cats with OSCC were compared with an age‐matched control sample of client‐owned cats and cats with CGS or PD. Owners of cats completed an anonymous questionnaire including demographic, environmental and lifestyle information. Results On multivariable logistic regression, covariates significantly associated with an increased risk of OSCC were rural environment (OR: 1.77; 95% CI: 1.03‐3.04; P = .04), outdoor access (OR: 1.68; 95% CI: 1.07‐2.63; P = .02), environmental tobacco smoke (OR: 1.77; 95% CI: 1.05‐3; P = .03), and petfood containing chemical additives (OR: 1.98; 95% CI: 1.04‐3.76; P = .04). Risk factors shared with CGS and PD were outdoor access and petfood containing chemical additives, respectively. A history of oral inflammation was reported in 35% of cats with OSCC but did not emerge as a risk factor. Conclusions and Clinical Importance The study proposes novel potential risk factors for OSCC in cats. Although a history of inflammatory oral disease was not significantly more frequent compared with random age‐matched controls, OSCC shared several risk factors with CGS and PD.

The prognostic significance of internal tandem duplication (ITD) mutations in exons 8 and 11 of c-kit has been well-described for canine cutaneous mast cell tumors (MCTs), but c-kit mutations have rarely been reported in subcutaneous MCTs. The objective of this study was to identify the prevalence of ITD mutations in exons 8 and 11 of c-kit in canine subcutaneous MCTs and to investigate its association with histologic grade, KIT pattern, and proliferation markers. ITD mutations in exons 8 and 11 of c-kit, mitotic count, Ki67 index, AgNOR number, Ki67xAgNOR score, KIT pattern, and histologic grade (two-tier system) were retrospectively recorded for 216 dogs with subcutaneous MCTs. ITD mutations in exons 8 and 11 of c-kit were detected in 23 (10.6%) and 12 (5.56%) subcutaneous MCTs, respectively. Exon 11 mutations were significantly associated with Kiupel high grade (p < 0.001) and increased mitotic count (p < 0.001) compared to subcutaneous MCTs with no mutations in exons 8 or 11 (p = 0.002) or subcutaneous MCTs with a mutation in exon 8 (p = 0.001). There was no significant association of either c-kit mutation with KIT patterns or proliferation activity. This study identified a higher prevalence of ITD mutations in exons 8 and 11 of c-kit in subcutaneous MCTs than previously reported. Like their cutaneous counterpart, subcutaneous MCTs with exon 11 mutations were more likely to be histologically high grade and have a higher mitotic count, whereas such associations were not observed in subcutaneous MCTs with exon 8 mutations.

The genomic landscape in human B-cell lymphoma has revealed several somatic mutations and potentially relevant germline alterations affecting therapy and prognosis. Also, mutations originally described as somatic aberrations have been shown to confer cancer predisposition when occurring in the germline. The relevance of mutations in canine B-cell lymphoma is scarcely known and gene expression profiling has shown similar molecular signatures among different B-cell histotypes, suggesting other biological mechanisms underlining differences. Here, we present a highly accurate approach to identify single nucleotide variants (SNVs) in RNA-seq data obtained from 62 completely staged canine B-cell lymphomas and 11 normal B-cells used as controls. A customized variant discovery pipeline was applied and SNVs were found in tumors and differentiated for histotype. A number of known and not previously identified SNVs were significantly associated to MAPK signaling pathway, negative regulation of apoptotic process and cell death, B-cell activation, NF-kB and JAK-STAT signaling. Interestingly, no significant genetic fingerprints were found separating diffuse large B-cell lymphoma from indolent lymphomas suggesting that differences of genetic landscape are not the pivotal causative factor of indolent behavior. We also detected several variants in expressed regions of canine B-cell lymphoma and identified SNVs having a direct impact on genes. Using this brand-new approach the consequence of a gene variant is directly associated to expression. Further investigations are in progress to deeply elucidate the mechanisms by which altered genes pathways may drive lymphomagenesis and a higher number of cases is also demanded to confirm this evidence.

Background Regional lymph nodes are frequently sampled in cats with suspected intestinal lymphoma; however, their diagnostic value has not been explored. Objectives To investigate whether histologic and immunohistochemical analysis of mesenteric lymph nodes correlates with the diagnosis of intestinal lymphoma in cats. Animals One hundred 2 client‐owned cats diagnosed with intestinal lymphoma. Methods Retrospective study. The inclusion criteria required a full‐thickness biopsy of the small intestine and concurrent excision of mesenteric lymph nodes. Histologic and immunophenotypic analyses were performed on intestinal biopsies and corresponding lymph nodes. Selected nodal samples diagnosed with reactive lymph nodes underwent clonality testing. Results Transmural T‐cell lymphomas, encompassing small and large cell types, were predominant (64 cases, 62.7%), with large B‐cell lymphomas being more frequently transmural (68.8%) than mucosal (31.2%). Among all lymph nodes examined, 44 (43.1%; 95% CI: 33.9%‐52.8%) exhibited neoplastic infiltration. Among cases of small cell lymphoma, 51 out of 72 (70.8%; 95% CI: 59.4%‐80.1%) showed no nodal involvement. Clonality results correctly identified 19/30 (63.3%; 95% CI: 45.5%‐78.2%) reactive lymph nodes. Concerns were raised regarding clonal identification in the remaining cases and potential misdiagnoses based on phenotypic characteristics. Conclusion and Clinical Importance The study underscores the potential drawbacks of relying solely on mesenteric lymph nodes for diagnosing intestinal lymphomas in cats, particularly small cell subtypes. It emphasizes the importance of full‐thickness biopsies for assessing transmural infiltration and recommends caution when utilizing mesenteric lymph nodes for histologic, immunohistochemical and clonality evaluations in mucosal lymphomas. Despite limitations, this research highlights the need for comprehensive diagnostic strategies in cats with intestinal lymphoma.

Background Cytopathology is a minimally invasive and convenient diagnostic procedure, often used as a substitute for histopathology to diagnose and characterize lymphoma in dogs. Objectives Assess the diagnostic performance of cytopathology in diagnosing lymphoma and its histopathological subtypes in dogs. Animals One‐hundred and sixty‐one lymph node samples from 139 dogs with enlarged peripheral lymph nodes. Methods Based only on cytopathology, 6 examiners independently provided the following interpretations on each sample: (a) lymphoma vs nonlymphoma; (b) grade and phenotype; and (c) World Health Organization (WHO) histopathological subtype. Histopathology and immunohistochemistry (IHC) findings were used as reference standards to evaluate diagnostic performance of cytopathology. Clinical, clinicopathologic, and imaging data also were considered in the definitive diagnosis. Results Classification accuracy for lymphoma consistently was >80% for all examiners, whereas it was >60% for low grade T‐cell lymphomas, >30% for high grade B‐cell lymphomas, >20% for high grade T‐cell lymphomas, and <40% for low grade B‐cell lymphomas. Interobserver agreement evaluated by kappa scores was 0.55 and 0.32 for identification of lymphoma cases, and of grade plus immunophenotype, respectively. Conclusions and Clinical Importance Cytopathology may result in accurate diagnosis of lymphoma, but accuracy decreases when further characterization is needed. Cytopathology represents a fundamental aid in identifying lymphoma and can be used as a screening test to predict grade and phenotype. However, these results must be confirmed using other ancillary techniques, including flow cytometry, histopathology, and immunohistochemistry (IHC).

Background Spontaneous tumors in dog have been demonstrated to share many features with their human counterparts, including relevant molecular targets, histological appearance, genetics, biological behavior and response to conventional treatments. Mammary tumors in dog therefore provide an attractive alternative to more classical mouse models, such as transgenics or xenografts, where the tumour is artificially induced. To assess the extent to which dog tumors represent clinically significant human phenotypes, we performed the first genome-wide comparative analysis of transcriptional changes occurring in mammary tumors of the two species, with particular focus on the molecular pathways involved. Results We analyzed human and dog gene expression data derived from both tumor and normal mammary samples. By analyzing the expression levels of about ten thousand dog/human orthologous genes we observed a significant overlap of genes deregulated in the mammary tumor samples, as compared to their normal counterparts. Pathway analysis of gene expression data revealed a great degree of similarity in the perturbation of many cancer-related pathways, including the 'PI3K/AKT', 'KRAS', 'PTEN', 'WNT-beta catenin' and 'MAPK cascade'. Moreover, we show that the transcriptional relationships between different gene signatures observed in human breast cancer are largely maintained in the canine model, suggesting a close interspecies similarity in the network of cancer signalling circuitries. Conclusion Our data confirm and further strengthen the value of the canine mammary cancer model and open up new perspectives for the evaluation of novel cancer therapeutics and the development of prognostic and diagnostic biomarkers to be used in clinical studies.

TP53 mutations are associated with short survival and poor treatment response in canine diffuse large B-cell lymphoma (cDLBCL). The expression of TP53 by RNAscope ® in situ hybridization and p53 by immunohistochemistry (IHC) was investigated in 37 formalin-fixed paraffin-embedded cDLBCL, to assess their correlation with TP53 mutational status and to evaluate their prognostic value. TP53 was detected in all samples by RNAscope ® . Ten of 37 (27%) cases expressed p53 by IHC, with highly variable percentage of positive cells. TP53 RNAscope ® scores and p53 IHC results were not correlated. The expression of TP53 by RNAscope ® was not influenced by its mutational status. Conversely, p53 IHC and TP53 mutations were significantly associated. p53 IHC predicted TP53 genetic mutations with high accuracy (97.3%). All TP53-mutated samples carrying missense mutations exhibited p53 expression by IHC, while all wild-type cases and a single case with frameshift insertion were negative. In univariable analysis, p53 IHC was associated with shorter time to progression (TTP) and lymphoma-specific survival (LSS). Nevertheless, in multivariable analysis, only treatment significantly affected TTP and LSS. These findings suggest p53 IHC is an accurate, cost-effective tool for predicting TP53 mutations in cDLBCL, unlike TP53 RNAscope ® , though its prognostic value requires further validation.

Chemotherapy and cyclooxygenase inhibitors (COXi) are primary treatments for canine urethral transitional cell carcinoma (uTCC), a tumor known for its aggressiveness and poor prognosis. This retrospective study aimed to evaluate the clinico-pathological characteristics, treatment modalities, and prognostic factors of 35 dogs with confirmed uTCC that received chemotherapy and COXi. Upon admission, urethral obstruction (UO) and urinary tract infection (UTI) were observed in seven (20%) dogs each. Gemcitabine (n = 20; 57.1%) and vinblastine (n = 10; 28.6%) were commonly used as first-line therapies, with four dogs also receiving radiation therapy. Based on RECIST, one (2.9%) dog achieved complete remission, nine (25.7%) partial remission, 20 (57.14%) showed stable disease, and five (14.3%) progressed. Among dogs with UO, six (85.7%) showed resolution or improvement after the first chemotherapy dose. The median time to local progression was 171 days (range: 107–235), and the median survival time was 333 days (range: 158–508). Dogs with UO upon admission had a higher risk of local progression, while both UO and UTI were associated with an increased risk of overall disease progression and tumor-related death. Additionally, gemcitabine significantly improved metastatic control. This study identified UO and UTI as negative prognostic factors, highlighting the importance of a multimodal approach in managing uTCC.